Inflammation is a significant component in a number of skin disorders or diseases including, but not limited to, acne and rosacea, atopic dermatitis, contact dermatitis, drug eruptions, psoriasis, seborrheic dermatitis, connective tissue diseases (such as lupus, scleroderma, and rheumatoid arthritis), other autoimmune disorders such as the blistering disease bullous pemphigoid or pemphigus, pigmentary diseases (such as post inflammatory hyperpigmentation, melasma and vitiligo), urticaria or hives, inflammation associated with skin infections such as tinea corporis or fungal infection of the finger or toenails, among others.
Modulating the inflammatory response has been shown to result in dramatic improvement in the conditions listed above. Standard treatment involves the use of topical corticosteroids, oral corticosteroids and other agents that modulate inflammation.
However, topical corticosteroids have undesirable side effects such as skin atrophy, telangiectasia, and the possibility of adrenal axis suppression thus limiting their long-term use.
Significant research has been conducted in the field of radiation therapy to assess the ability of free-radical scavengers in protecting normal tissue from ionizing radiation.
Sulfhydryl compounds were among the first radioprotectors to be identified. Their protective mechanism appears to be due to their ability to scavenge radiation-induced free radicals and/or donate reducing equivalents to oxidized molecules.
Hematopoietic cytokines have also been investigated as radioprotectors. They are believed to protect by more quickly restoring hematopoietic function after radiation exposure.
Recently, a new class of radioprotectors, referred to as nitroxides, has been described. As a class, nitroxides are stable free radical components which react with a variety of biologically relevant compounds including other free radicals (Nilsson et al. J. Biol. Chem., 1989, 264:11131-11135). The observation that several nitroxides themselves reacted with free radicals, specifically oxy radicals, led to the investigation of these compounds as radioprotectors (Saminu et al. Free Radical Biol. Med., 1989, 6:141-148).
Tempol [4-hydroxy-2,2,6,6-tetramethyl-piperidinyloxy, free radical] is one such example, a piperindinyl-n-oxyl with the n-oxide sterically stabilized by symmetric pairs of adjacent methyl groups. This compound is commercially available through Aldrich Chemical Co., Milwaukee, Wis. It is most commonly used to spin label biological molecules such as NADP.
Tempol has been demonstrated to function as a superoxide dismutase (SOD) mimic, protecting mammalian cells from superoxide generated from hypoxanthine/xanthine oxidase and from hydrogen peroxide mediated cytotoxicity (Mitchell et al. Biochem., 1990, 29:2802-2807; Samuni et al., J. Biol. Chem., 1988, 263:17921-17924). Tempol has also been demonstrated to provide both in vitro and in vivo protection against ionizing radiation (Mitchell et al. Arch. Biochem. Biophys., 1991, 289:62-70) and to protect against radiation-induced alopecia by speeding the recovery of hair growth within a field of heavily irradiated skin (Goffman et al. Int. J. Rad. Onc. Biol. Phys., 1992, 22:803-806). This protection has been suggested to be linked to direct protection of hair follicle stem cells and development of other nitroxides.
U.S. Pat. No. 5,840,734 describes the use of Tempol in prevention of photoaging, sunburn and skin cancer caused by the UVA and UVB rays of sunlight. Additionally, U.S. Pat. No. 6,552,040 describes using other nitroxides in addition to Tempol for photoprotection, and describes using nitroxides including Tempol to augment wound healing.
Nitroxides are stable free radicals with antioxidant catalytic activities similar to superoxide dismutase. Nitroxides existing in vivo have been shown to interact with other substances to also mimic catalase activities.
Nitroxide containing compounds have been described in the art for numerous uses. For example, U.S. Pat. No. 5,462,946 discloses biologically compatible compositions containing an effective amount of a metal independent nitroxide compound for use in protecting the skin against ionizing radiation, mucositis, the effects of whole body radiation and radiation induced hair loss. The nitroxide containing compositions disclosed therein are applied topically as an ointment, lotion or cream, intravenously or orally by pill or lozenge. This patent also teaches the nitroxide containing compounds to be useful as protectants against increased oxygen exposure so as to avoid pulmonary adult respiratory distress syndrome, oxygen-induced lenticular degeneration and hyaline membrane disease in infants, oxidative stress-induced cataracts, reperfusion injury in treating cardiovascular phenomena such as myocardial infarction and strokes, pancreatitis or intestinal ulceration and organ transplant, cytotoxicity due to excess oxidation in animal or plant cell cultures, cytotoxic effects of chemotherapeutic agents, and mutagenic and carcinogenic agents. Also taught in U.S. Pat. No. 5,462,946 is parenteral, intra-articular or oral administration of a nitroxide containing composition in arthritic conditions, parenteral or oral administration of a nitroxide containing composition as an aging retardant and oral or intravenous administration of a nitroxide containing compound in weight reduction.
U.S. Pat. No. 5,824,781, U.S. Pat. No. 5,840,701 and U.S. Pat. No. 5,817,632 teach compositions and processes to alleviate free radical toxicity based on use of nitroxides in association with physiologically compatible macromolecules. These compositions are suggested to be useful as blood substitutes, radioprotective agents, imaging agents, agents to protect against ischemia and reperfusion injury, particularly cerebral stroke, and in vivo enzyme mimics.